Review Article

Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

Table 1

Aberrant expression of molecules associated with Wnt signaling activity in autoimmunity diseases.

ADsWnt signalingKey signaling moleculeModelsEvaluated factor(s)Effect/mechanismReference(s)

RACanonical pathwaySFRP4Rat RA modelMeCP2Downregulating β-catenin by activating SFRP4 in RA rats[34]
GSK3βMSCsTNF-αAmeliorating inflammatory responses[43]
DKK1MSCsNF-κBSuppressing Wnt signaling by upregulating DKK1; inhibiting inflammatory responses, and promoting bone resorption and formation[44, 45]
Wnt1, TCF/LEF1, SPRP1FLSproMMP3; fibronectinAn enhanced Wnt signaling promotes RA progression[18]
Wnt1; WISP3FLS; synovial tissueInflammatory cytokinesHigh levels of Wnt1, Fzds, and WISP3 in RA tissues[46]
PKC mediated noncanonical pathwayWnt5a/Fzd5FLSIL6; IL15; RANKL; NF-κBContributing to the activated state of FLS in RA[47]
Wnt signalingWnt7bCartilage, bone, and synovium in RA and OA samplesTNF-α
IL-1b; IL-6
Evidence of an involvement of Wnt signaling in the pathobiology of both RA and OA[48]
Wnt10bMouseCD28 T cellsInhibition of CD28 costimulation by CTLA-4Ig promotes T cell Wnt10b production and bone formation[49]

ASWnt signalingDKK1Jurkat T cellsTNF-αDownregulating Wnt signaling by increasing DDK1 expression and ameliorating inflammatory responses[50]
Wnt signalingChondrocytesInduces differentiation of mesenchymal cells into osteoblast lineagesActive Wnt signaling contributes to osteophyte formation and joint remodeling[7]
Noncanonical pathwayWnt5a, Wnt10bMSCsTNF-αTNF-α induced Wnt5a and Wnt10b may be involved in the effects of inflammation on bone formation[51]

SSc Wnt signalingWnt2, Wnt3a, Wnt5a, Wnt10b, DDK2, LEF-1, WIF-1, β-cateninSkin biopsies and peripheral blood samples from SSc patients and mouse modelTGF-β; IL4; IL13; IL17; IL33; IFN; IL13An enhanced Wnt signaling promotes disease progression[19, 52, 53]
Wnt1, Wnt10b and DKK1B cells, mouse modelIL6The activation of Wnt signaling or inhibition of DKK1 induces severe fibrosis and lipoatrophy in animal models[54]
WIF-1, β-cateninFibroblasts from SScATF3; HDAC3An oxidative DNA damage induced by SSc autoreactive antibodies enables 
Wnt activation that contributes to fibrosis
[55]

AACanonical pathwayGSK3β, Wnt10bNK cellsIFN-γA decreased Wnt signaling impairs anagen initiation and the ability of stem cells to drive differentiation of hair keratinocytes[56]
Wnt signalingβ-catenin, Wnt7aC3H/HeJ mouse model of AAWnt signalingVitamin A enhances Wnt signaling to activate hair follicle SCs[57]

CCLNoncanonical pathwayWnt5a, ROR1HEK293 cells, leukemia B-1 cellsNF-κBROR1 promotes CLL cells to receive survival signals
[58]
Canonical pathwayWnt/β-cateninLeukemia B-1 cells, MEC-1 cells, CCL clinical samplesIL-6, inflammatory factorsQuercetin or metadherin inhibits leukemia cell expansion by blocking Wnt/β-catenin pathway and diminishes production of inflammatory factors in ADs and neoplasia[5961]

CIAWnt signalingFzd2PGRN-deficient TregsTNF-αWnt signaling contributes to the PGRN regulation of Tregs[62]

EAUCanonical pathwayDKK3, SFRP2RGMIL17Wnt inhibitors DKK3 and SFRP2 are downregulated in EAU; an enhanced Wnt signaling is involved in ERU pathogenesis[6, 63]

IBD Canonical pathway TCF4CD patientsPolymorphism analysisCorrelation of a functional variant TCF6 with early onset ileal CD[64]
TCF1, LRP6Paneth cellsAlpha-defensins HD-5 and HD-6A TCF-1-mediated Wnt signaling may contribute to the barrier dysfunction in CD[65]
LRP6CD patientsPolymorphism analysisCorrelation of a functional variant LRP6 with early onset ileal CD[33]

JRACanonical pathwayWnt3a, WISP3, TCF1SFMCs, Treg cellsFOXP3 A dysregulated 
Wnt signaling in the synovium inhibits Treg cell function and promotes JIA pathogenesis
[42]

MSWnt signalingWnt3a, Wnt5a, ROR2, β-cateninEAE miceMechanical hyperalgesia and allodynia of paws in EAE miceAn aberrant activation of Wnt signaling contributes to the development of EAE-related chronic pain[12]

PsoriasisCanonical pathwayActivates Wnt signaling by LiClManic-depressive patientsThyroid microsomal antibodiesLiCl induced thyroid dysfunction and abrogated Treg cells suppressive capacity[66]
Wnt signalingWnt5a, Fzd2, Fzd5, DKKs, WIF-1Biopsies of psoriasis patientsIL-1α, TNF-α, IFN-γ, TGF-αCanonical Wnt signaling toward noncanonical pathways driven by interactions between Wnt5a and its cognate receptors in psoriasis, accompanied by impaired homeostatic inhibition of Wnt signaling by WIF-1 and dickkopf[67]

SLECanonical pathwayDKK1BM-MSCsTNF-αWnt signaling plays a critical role in the senescence of SLE BM-MSCs through the p53/p21 pathway[68]

T1DMCanonical pathwayGSK3βINS-1E rat insulinoma cells, rat islets Cell proliferation and survivalAn enhanced Wnt signaling by inhibiting CSK3 promotes β-cell proliferation[69, 70]

UIPNoncanonical pathwayWnt5aPrimary fibroblasts of lung tissues with UIPFibronectin, α5-integrin, β-cateninWnt5a promotes fibroblast proliferation in IPF and UIP[71]

AA: alopecia areata; ATF3: activating transcription factor 3; AS: ankylosing spondylitis; BM-MSCT: bone marrow-mesenchymal stem cell transplantation; CD: Crohn’s disease; CIA: collagen-induced arthritis; CLL: chronic lymphocytic leukemia; CTL: cytotoxic T lymphocytes; EAE: experimental autoimmune encephalomyelitis; EAU: experimental autoimmune uveitis; ERU: equine recurrent uveitis; FLS: fibroblast-like synoviocytes; HDAC3: histone deacetylase 3; IPF: idiopathic pulmonary fibrosis; JRA: juvenile idiopathic arthritis; MEC: mucoepidermoid carcinoma cell; MeCP2: methyl-CpG-binding protein 2; MS: multiple sclerosis; MSCs: mesenchymal stem cells; NF-κB: nuclear factor-kappa B; PBMCs: peripheral blood mononuclear cells; PGRN: progranulin; RA: rheumatoid arthritis; RANKL: receptor activator of nuclear factor kappa B ligand; RMG: retinal Müller glial cells; SCDH: spinal cord dorsal horn; SFMCs: synovial fluid mononuclear cells; SFRP4: frizzled-related protein 4; SLE: systemic lupus erythematosus; SSc: systemic sclerosis; TGF-: transforming growth factor ; T1DM: type 1 diabetes mellitus; TNF-α: tumor necrosis factor alpha; WISP3: Wnt1-inducible signaling pathway protein 3; UIP: usual interstitial pneumonia.